tbuckley/cabot-search huggingface dataset:
PCV VS. LOMUSTINE FOR PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Isata Fofanah, Thomas Pigott, Julie Mansell, Michael Flatley, Paul Hatfield, Suchandana Bhaumik, Susan Short, Louise Murray
Journal: Neuro-Oncology (2023)

Abstract AIMS Almost all patients with glioblastoma relapse after initial treatment. At relapse, chemotherapy using multi-agent PCV (Procarbazine, Lomustine and Vincristine) or single agent Lomustine is often employed. Lomustine is an oral agent, and therefore spares patients from additional hospital visits for intravenous vincristine and removes the need for dietary restrictions while taking procarbazine, and so would be an attractive option, especially if there was no difference in survival compared to PCV. There are currently no data regarding whether PCV or Lomustine is superior. This project examines survival in patients treated with PCV or Lomustine for recurrent glioblastoma. METHOD A retrospective study was performed including patients treated at Leeds Cancer Centre between January 2015 and December 2019. Patients had a histological diagnosis of glioblastoma and received (chemo)radiotherapy at initial presentation. PCV or Lomustine was used at recurrence. Factors predictive of overall survival (OS) were investigated. RESULTS 116 patients were included (66 received PCV, 50 received Lomustine). Performance status (PS) was 0, 1 and 2/3 in 22, 59 and 35, respectively. Median OS from first PCV or lomustine was 5.7 months (95% confidence interval: 5.1-6.3). The median number of cycles was 2 for both PCV and Lomustine with 115/116 (99%) discontinuing treatment due to disease progression. On univariate analysis, PS and type of chemotherapy were statistically significant. On multivariate analysis, only PS remained significant. CONCLUSIONS After adjusting for PS, there was no statistically significant difference in OS for patients treated with PCV or Lomustine. This finding has treatment implications and requires validation in a larger cohort.
PLASMA PROTEOMICS AND MACHINE LEARNING FOR NOVEL BIOMARKER DISCOVERY IN ADULT MALIGNANT GLIOMA
Authors: Henriette Pedersen, Kirstine Juul Elbæk, Michael Wodstrup Vandborg, Yi Chieh Lim, Aleena Azam, Sarah Skovlunde Hornshøj Pedersen, Jane Skjøth-Rasmussen, Erwin Schoof, Petra Hamerlik
Journal: Neuro-Oncology (2023)

Abstract AIMS Plasma is a valuable source for identifying non-invasive biomarkers, and when combined with an examination of the highly dynamic proteome, it has the potential to lead to the identification of novel biomarkers in glioma. The aim of this study was to uncover plasma-based protein biomarkers for adult malignant glioma. METHOD Mass spectrometry-based proteomics with tandem mass tag (TMT) labelling of plasma from healthy individuals and adult malignant gliomas was performed. A differential abundance analysis was carried out to identify proteins that were deregulated in primary gliomas compared to healthy individuals. Machine learning was employed to identify a diagnostic biomarker panel. RESULTS When comparing plasma from healthy individuals to that of primary gliomas, several high and low abundant proteins were found to be deregulated. To improve the accuracy and ability of biomarkers to detect malignant gliomas, machine learning was employed and led to a development of a classifier, which performed with high accuracy, specificity, and sensitivity. CONCLUSIONS The discovery of a plasma-based protein classifier, once validated, may facilitate an earlier diagnosis of glioma patients, and thereby reduce time-to-treatment.
ANTI-SEIZURE MEDICATION IN GLIOMA PATIENTS: GETTING IT RIGHT fiRST TIME
Authors: Morag Brothwell, Jennifer Collins, Louise Dulley
Journal: Neuro-Oncology (2023)

Abstract AIMS Seizures affect between 60–90% patients with low grade glioma and between 40–60% patients with high grade glioma. There are no national guidelines for seizure management in glioma patients. This quality improvement project investigated the initiation of anti-seizure medication in glioma patients with new-onset seizures. METHOD A retrospective review was undertaken of new glioma patients’ electronic notes (2020-2022) seen in Oncology clinic at Colchester hospital. RESULTS Thirty-seven patients (twenty-five glioblastoma IDH-wt, two grade 3 astrocytoma IDH-mutant, one grade 2 astrocytoma IDH-mutant, three oligodendroglioma IDH-mutant, six radiological diagnoses of glioma) were included. Following neurosurgical discharge, twenty-three did not need anti-seizure medication, three had long standing anti-seizure medication which was not changed, one patient was advised to stop phenytoin medication after surgery, four patients were on levetiracetam 500mg twice daily and six patients were on levetiracetam 250mg twice daily, with no dose escalation plan in place. Three of these six patients were subsequently hospitalised with seizures, one of which interrupted chemoradiation. None of the four patients on 500mg BD were hospitalised with seizures. CONCLUSIONS This project highlights the need for local anti-seizure guidelines for new glioma patients, which should include consideration of personalised drug choice, dependent on seizure type and demographics. Patients should be escalated to the therapeutic levetiracetam dose to decrease the risk of morbidity from seizures. This supports the need for national guidelines on anti-seizure medication with neurology collaboration.
A CASE ILLUSTRATION AND LITERATURE REVIEW OF THYROID CANCER METASTASIS TO THE PITUITARY FOSSA
Authors: Damjan Veljanoski, Agbolahan Sofela, Abdel-Rahman Abdel-Fattah, Aditya Shivane, Samiul Muquit
Journal: Neuro-Oncology (2023)

Abstract AIMS To understand the clinico-radiological and histopathological features, treatment strategies and outcomes of patients with thyroid cancer metastasis to the pituitary fossa. METHOD A 71-year-old man presented with a few months’ history of headaches, blurred vision, diplopia and right sided ptosis. MRI head revealed a 2.5cm pituitary fossa lesion distorting the optic chiasm with right sided cavernous sinus invasion. It also showed frontal, temporal and parieto-occipital lesions. CT thorax, abdomen and pelvis found a retrosternal thyroid goitre. An open biopsy of the occipital lobe lesion revealed a metastatic papillary adenocarcinoma from the thyroid gland. An ultrasound-guided fine needle aspiration of the goitre and abnormal level IV lymph nodes revealed Thy5. The patient subsequently underwent an endoscopic transsphenoidal resection of the pituitary tumour which was confirmed to be a carcinoma. A date and language unrestricted literature search was performed across the MEDLINE, Embase (via Ovid) and Scopus databases using keywords relating metastasis, the pituitary &amp; thyroid glands, and the brain. Citations reporting patients with thyroid metastasis to the pituitary fossa were included. A predetermined proforma was used to extract and store data from the included citations. RESULTS After de-duplication, 2,833 citations were screened for eligibility and 42 citations met the inclusion criteria. CONCLUSIONS We present a rare case illustration and literature review of patients with thyroid cancer metastasis to the pituitary fossa.
WHAT ROLE CAN A PERSONAL TRAINER PLAY IN IMPROVING QUALITY OF LIFE THROUGHOUT ONCOLOGY TREATMENT FOR PEOPLE WITH A BRAIN TUMOUR
Authors: Ellie Kostick, Victoria Hurwitz, Jessica La, Charlotte Robinson, Aeron Suarez, Sarah Hedges, Renata Fukuthi, Nicola Harding, Lucy Brazil, Angela Swampillai, Kazumi Chia, Vishal Manik, Olivia Africa, Rebecca Clark, Omar Al-Salihi
Journal: Neuro-Oncology (2023)

Abstract AIMS Review of a single person case study to establish if a personal trainer (PT) could help build a personalised pro- gramme for people with brain tumours going through oncology treatment. The aim being to help manage resilience both physically and psychologically through treatment and improve quality of life. METHOD A young person who has completed radiotherapy and chemotherapy after surgical debulking of a brain tumour was contacted. He worked as a PT before diagnosis and continued throughout treatment. He gradually increased his exercise tolerance and tailored exercises to different days of the treatment cycle to match his needs. He managed his fatigue and gradually built his exercise tolerance up back to baseline and continue with treatment. RESULTS This patient created a ‘patient guide’ with suggested exercises from his unique perspective as a person who has been through treatment and as a PT. CONCLUSIONS This guide has not yet been trialled with the rest of the patient population. The hope is that this will be used to guide further research in this field and may lead to the implementation of a permeant PT member of staff to the oncology service. In his words ‘this is just an example of my journey and how I stumbled my way through the diffculty of a cancer diagnosis and subsequent treatment. If you can take something away and apply it to your own situation then that’s brilliant’, ‘each day is a testament to how well you’re doing’
SURVIVAL OVER A DECADE IN A CASE OF GLIOBLASTOMA
Authors: Omar Shawki, Salman Shaikh, Soumya Mukherjee, Hussien El-Maghraby, Ronan Dardis
Journal: Neuro-Oncology (2023)

Abstract AIMS Glioblastoma multiforme is the most aggressive type of primary brain tumours, but there is a small percentage of patients who have a long-term survival and some exceptional cases who survive decades after surgical removal of tumour along with adjuvant therapy. METHOD In 2011, a 40-year-old man, presented with headaches &amp; confusion and underwent gliolan guided resection of a right frontal glioblastoma WHO grade IV. He received 30# of 60Gy Radiotherapy with TMZ. Chemotherapy was continued with interval scans in 2016 and 2018 showing stable disease. MRI scan in October 2022 showed contrast enhancing foci for which redo surgery was eventually performed 5 months later. The repeat histology is pending. 12 years after the primary diagnosis, the patient is clinically well. RESULTS Only a very handful cases of glioblastoma show prolonged survival of over 10 years. The long-survival for glioblastoma multiforme can be linked to age, surgical resection, molecular profile and good performance score before surgery. CONCLUSIONS These extremely rare scenarios of prolonged survival in glioblastoma serves as a motivation to continue incessant research in this field with the hope of improving life expectancy in grade 4 tumours.
TUMOUR TREATING FIELDS (TTFIELDS) THERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA: A META-ANALYSIS AND SYSTEMATIC REVIEW OF REAL-WORLD SURVIVAL DATA
Authors: Matthew Ballo, Patrick Conlon, Gitit Lavy-Shahaf, Noa Urman, Adrian Kinzel, Josef Vyamzal, Aaron Rulseh
Journal: Neuro-Oncology (2023)

Abstract AIMS Tumour Treating Fields (TTFields) are electric fields that disrupt processes required for cancer cell viability and tumour progression. TTFields therapy gained FDA approval and CE accreditation for newly diagnosed glioblastoma (ndGBM) following the EF-14 study (NCT00916409). We aimed to determine the real-world survival benefit of TTFields therapy. METHOD Survival data from clinical studies in TTFields therapy-treated patients with ndGBM were identified using a literature search and analysed. The Cochran Q test and Higgins I2 statistic were used to assess and quantify inter-study heterogeneity. Survival curves were pooled using a distribution-free random-effects method. RESULTS Among studies evaluating the clinical effcacy of TTFields therapy in ndGBM, six studies were identified which compared the addition of TTFields therapy to standard of care (SOC) vs SOC alone. The meta-analysis showed a significant improvement in OS for TTFields therapy-treated patients vs SOC alone (P &amp;lt; 0.001). The pooled effect was robust and independent of any individual study. In post-approval studies, the pooled median OS was 22.2 months (95% CI, 17.3–42.6) and 17.3 months (95% CI, 13.6–22.0) for TTFields therapy-treated patients and SOC, respectively. Rates of gross total resection were generally higher in the real-world setting, irrespective of TTFields therapy use. Average device usage of ≥75% was associated with prolonged survival vs &amp;lt;75% usage (pooled HR: 0.63; 95% CI, 0.48–0.83; P = 0.001). CONCLUSIONS Data suggest a significant survival benefit when TTFields therapy is added to SOC for patients with ndGBM. Usage of ≥75% may be meaningful in the real-world setting.
TESSA JOWELL BRAIN MATRIX PLATFORM STUDY: PRELIMINARY ANALYSIS OF THE PRIMARY FEASIBILITY &amp; PROCESS-CENTRED OBJECTIVE
Authors: Colin Watts, Amit Patel, Joshua Savage, Olaf Ansorge, Victoria Wykes, Yvonne Wallis, Rowena Sharpe, Rhys Mant, Hannah Brooks, Susan Short, Keyoumars Ashkan, Paul Brennan, Anthony Chalmers, Stuart Smith, Michael Jenkinson, Catherine McBain, Adam Waldman, Gerard Thompson, Lucinda Billingham
Journal: Neuro-Oncology (2023)

Abstract AIMS The Tessa Jowell BRAIN MATRIX (ISRCTN14218060) is an ongoing platform study, collecting disease, treatment, and outcome data prospectively in glioma patients, across nine UK hospitals. We report a preliminary analysis of the primary feasibility and process-centred objectives. METHOD Primary Objective: Test the feasibility of establishing an integrated histological-molecular diagnosis using Whole Genome Sequencing (WGS) and Epigenomic Classification (EC) (‘Heidelberg Classifier’) data in NHS practice within 28 days. Primary Outcome: Time (from surgery) to integrated histological–molecular diagnosis (TTMD) using WGS and EC. Secondary Outcome: Time to completion of each node (stage) of the tissue and imaging pathway. RESULTS Data snapshot on 23-Feb-2023 confirmed 250 patients recruited. Nine nodes along the tissue &amp; imaging pathway were defined. Twenty-one patients had completed the pathway and time to each node was calculated. Median time to complete the pathway was 404 days (range 124-653). There was a trend of improvement in TTMD in recently recruited patients. CONCLUSIONS The patient pathway from surgery to clinical feedback through a Genomic Tumour Advisory Board (GTAB) utilises NHS-accredited pathways and protocols. Delays inherent in the pathway emphasise the urgent need for infrastructure and operational delivery improvements of the NHS Genomic Medicine Service for brain cancer patients as the current timeframe is not clinically relevant for informing patient care. These data also highlight geographical inequality in accessing genomic medicine within England, across the seven Genomic Laboratory Hubs, and the devolved nations. Detailed analysis of the delays at each node will identify opportunities and solutions to inform discussions with the NHS and Genomics England.
LONGITUDINAL WGS AND WES OF GLIOBLASTOMA REVEAL POTENTIAL PATHWAY TARGETS
Authors: Yousef Alghamdi, Georgette Tanner, Martina Finetti, Steven Pollock, Aruna Chakrabarty, Azzam Ismail, James Poulter, Lucy Stead
Journal: Neuro-Oncology (2023)

Abstract AIMS Treating glioblastoma (GBM) patients remains challenging as the current regimens result in the recurrence of a treatment-resistant and fatal tumour. We aimed to identify candidate pathways that, when mutated, confer treatment resistance. Targeting these pathways may improve GBM treatment effcacy. METHOD We performed WGS and WES on 46 matched primary and recurrent GBMs (the Discovery cohort) and used data from additional 188 samples from the Glioma Longitudinal AnalySiS consortium (GLASS: Validation cohort). First, we identified variants that were shared between primary and recurrent GBMs. We then highlighted those most likely to be involved in treatment resistance, i.e. with: 1) low allele fractions at primary and high in recurrent, 2) high allele fractions in both primary and recurrent. Finally, we performed enrichment analysis using these variants to identify pathways that may drive clonal expansion from primary to recurrent. RESULTS The analysis of variants that increased from primary to recurrent revealed three significant disrupted path- ways in the Discovery cohort; “Activation of BH3 Only Proteins” (Reactome), “P53 pathway” (BIOCARTA), and “Intrinsic Pathway for Apoptosis” (REACTOME). Six distinct genes caused the aberration of these pathways. The same pathways were significantly disrupted in the recurrent variants group of the Validation cohort but were solely caused by TP53 alterations. In the Discovery cohort, “Activation of BH3 Only Proteins” was altered in 24% of the patients. CONCLUSIONS Investigating how pathway mutations alter in GBM through treatment has led to identifying potential candidate mechanisms to be further studied in the laboratory.
INDIGO: A GLOBAL, RANDOMIZED, DOUBLE-BLINDED, PHASE 3 STUDY OF VORASIDENIB VERSUS PLACEBO IN PATIENTS WITH RESIDUAL OR RECURRENT GRADE 2 GLIOMA WITH AN IDH1/2 MUTATION
Authors: Catherine McBain, Ingo K Mellinghoff, Martin J van den Bent, Deborah T Blumenthal, Mehdi Touat, Katherine B Peters, Jennifer Clarke, Joe Mendez, Liam Welsh, Warren P Mason, Andreas F Hottinger, Juan M Sepulveda, Wolfgang Wick, Riccardo Soffetti, Patrick Y Wen, Timothy F Cloughesy
Journal: Neuro-Oncology (2023)

Abstract AIMS Current treatments grade 2 gliomas are not curative and can be associated with short- and long-term toxicities. Vorasidenib (VOR), an oral, brain-penetrant, dual inhibitor of mutant (m)IDH1/2 enzymes, has shown a tolerable safety profile and preliminary clinical activity in phase 1 studies. METHOD In the phase 3 INDIGO study (NCT04164901), patients (pts) were randomized 1:1 to receive VOR 40 mg daily or placebo (PBO) daily in 28-day cycles. Patients were stratified by 1p19q status and baseline tumor size. Key eligibility criteria included: age ≥12; KPS &amp;gt;80; residual or recurrent grade 2 IDH1m or IDH2m oligodendroglioma or astrocytoma; measurable non-enhancing disease; no prior treatment for glioma with most recent surgery 1-5 years from randomization; and not in immediate need of chemotherapy/radiation. Primary endpoint: radiographic progression-free survival (PFS) by blinded independent radiology committee (BIRC). Key secondary endpoint: time to next intervention (TTNI). RESULTS As of 06 Sep2022, 331 pts were randomized across 10 countries: 168 to VOR and 163 to PBO. Median PFS by BIRC was 27.7 mos with VOR and 11.1 with PBO (HR, 0.39; 95% CI, 0.27, 0.56; 1-sided P=0.000000067). Median TTNI was not reached with VOR and 17.8 mos with PBO (HR, 0.26; 95% CI, 0.15, 0.43; 1-sided P=0.000000019). All-grade adverse events (AEs) occurring in &amp;gt;20% pts receiving VOR vs PBO were alanine aminotransferase increased, COVID-19, fatigue, aspartate aminotransferase increase, headache, diarrhea, nausea. Common grade ≥3 AEs (&amp;gt;5%): ALT increased (9.6% vs 0%). CONCLUSIONS VOR significantly improved PFS by BIRC versus PBO with a manageable safety profile. © 2023 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2023 ASCO Annual Meeting. All rights reserved.
M6A RNA METHYLATION AS A THERAPEUTIC TARGET IN HIGH GRADE GLIOMA
Authors: Masar Radhi, Jonathan Rowlinson, Nigel Halliday, Dong-Hyun Kim, Simon Deacon, Helen Knight, Stuart Smith
Journal: Neuro-Oncology (2023)

Abstract AIMS High grade glioma (HGG) is a devastating brain cancer that has poor prognostic outcomes. N6-methyladenosine (m6A) is the most prevalent mRNA modification. It is co transcriptionally installed by a methyltransferase com- plex composed of METTL3, METTL14 and WTAP. The modification is reversible and erased by FTO and ALKBH5. Here we sought to investigate the functional importance of m6A RNA methylation in the pathogenesis and drug resistance of HGG. METHOD To identify the expression of key m6A effectors, RT-qPCR and immunofluorescence were undertaken . The expression of these effectors was modified using siRNA knockdown and small molecules to identify their effects on key transcription factors. The effect of modification on the ability of the cells to form neurospheres was also assessed. Developing chemotherapy-resistant cell lines is undertaking to assess the effect of m6A RNA levels on the ability of HGG cells to adapt to environmental changes. Measuring the m6A level was achieved by developing methylated RNA immunoprecipitation qPCR and LC-MS/MS techniques. RESULTS We found that key m6A RNA methylation effectors are highly expressed in HGG cell lines and tissues. LC-MS/MS and immunofluorescence showed an increase in the level of m6A. Genetic and chemical inhibition of METTL3, FTO and WTAP affects the expression of key transcription factors in self-renewal, cell cycle regulation and tumorigenesis. Depletion of these effectors reduces the ability of cells to form neurospheres, increases apoptosis and suppresses invasion. CONCLUSIONS These findings suggest the role of RNA methylation in the pathogenesis of HGG and could open a new avenue for developing effective treatment strategies.
DIFFERENTIAL CELL SURFACE PROTEOMICS OF FLOTILLIN-1, HMGB1 AND AMINOPEPTIDASE IN H3 MUTATED PAEDIATRIC HIGH-GRADE GLIOMA
Authors: Chloe Walugembe, Matthew Litchfield-Williams, Anya Snary, Robert Layfield, Farhana Haque
Journal: Neuro-Oncology (2023)

Abstract AIMS High-grade gliomas (HGG) are the deadliest central nervous system tumour in children. Despite this, treatment options remain elusive, leaving children with a dismal prognosis. Histone H3.3 mutations, K27M and G34V/R have been identified as the two most common recurrent somatic mutations in paediatric HGG (pHGG). These mutations are present in 50% of pHGG compared to only 1% in adults. Our previous research on cell membrane protein analyses have identified different signature of unique and common cell membrane proteins in H3-G34R/V mutated pHGG, in comparison to H3 wild type tumour. Among these we have identified flotillin-1, HMGB1 and aminopeptidase N. Flotillin-1 promotes numerous malignancies, High mobility group box 1(HMGB1) functions as an oncogene and aminopeptidase N is a cell surface metallo- protease involved in tumour progression. We have now verified the expression and localization of these cell surface proteins in H3 mutated and wildtype tumour, in order to target them for developing novel therapeutics. METHOD Cell membrane proteomics were further verified though mass-spectrometric data analyses. Expression and localization of flotillin-1, HMGB1 and Aminopeptidase in H3.3 mutated pHGG cell lines in comparison to H3 wildtype glioma were analysed, using different protein expression assays including immunofluorescence microscopy and western blot assays. RESULTS Experimental analyses showed differential protein expression and localization of Flotillin-1, HMGB1 and Aminopeptidase and verified the mass-spectrometric proteomic data in H3-G34V pHGG, in comparison to wild- type pHGG. CONCLUSIONS This new knowledge will help us utilise Flotillin-1, HMGB1 and Aminopeptidase N, as potential therapeutic targets for these unique H3 mutated children’s brain tumours.